High-altitude hypoxia exposure inhibits erythrophagocytosis by inducing macrophage ferroptosis in the spleen
Wan-ping Yang,
Mei-qi Li,
Jie Ding,
Jia-yan Li,
Gang Wu,
Bao Liu,
Yu-qi Gao,
Guo-hua Wang,
Qian-qian Luo
Affiliations
Wan-ping Yang
Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine and Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
Mei-qi Li
Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine and Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
Jie Ding
Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine and Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
Jia-yan Li
Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine and Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
Gang Wu
College of High-Altitude Military Medicine, Institute of Medicine and Hygienic Equipment for High Altitude Region, Army Medical University, Chongqing, China; Key Laboratory of Extreme Environmental Medicine and High-Altitude Medicine, Ministry of Education of China, Chongqing, China
Bao Liu
College of High-Altitude Military Medicine, Institute of Medicine and Hygienic Equipment for High Altitude Region, Army Medical University, Chongqing, China; Key Laboratory of Extreme Environmental Medicine and High-Altitude Medicine, Ministry of Education of China, Chongqing, China
Yu-qi Gao
College of High-Altitude Military Medicine, Institute of Medicine and Hygienic Equipment for High Altitude Region, Army Medical University, Chongqing, China; Key Laboratory of Extreme Environmental Medicine and High-Altitude Medicine, Ministry of Education of China, Chongqing, China
Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine and Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China; Department of Neurosurgery, Southwest Hospital, Army Medical University, Chongqing, China
Qian-qian Luo
Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine and Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
High-altitude polycythemia (HAPC) affects individuals living at high altitudes, characterized by increased red blood cells (RBCs) production in response to hypoxic conditions. The exact mechanisms behind HAPC are not fully understood. We utilized a mouse model exposed to hypobaric hypoxia (HH), replicating the environmental conditions experienced at 6000 m above sea level, coupled with in vitro analysis of primary splenic macrophages under 1% O2 to investigate these mechanisms. Our findings indicate that HH significantly boosts erythropoiesis, leading to erythrocytosis and splenic changes, including initial contraction to splenomegaly over 14 days. A notable decrease in red pulp macrophages (RPMs) in the spleen, essential for RBCs processing, was observed, correlating with increased iron release and signs of ferroptosis. Prolonged exposure to hypoxia further exacerbated these effects, mirrored in human peripheral blood mononuclear cells. Single-cell sequencing showed a marked reduction in macrophage populations, affecting the spleen’s ability to clear RBCs and contributing to splenomegaly. Our findings suggest splenic ferroptosis contributes to decreased RPMs, affecting erythrophagocytosis and potentially fostering continuous RBCs production in HAPC. These insights could guide the development of targeted therapies for HAPC, emphasizing the importance of splenic macrophages in disease pathology.
